MDM2 is an E3 ubiquitin-protein ligase that mediates ubiquitination of p53/TP53, leading to its degradation by the proteasome []. p53 acts as an important defense mechanism against cancer, and is negatively regulated by interaction with the oncoprotein MDM2 []. MDM2 overexpression correlates with metastasis and advanced forms of several cancers and may be used as a cancer drug target []. In addition, MDM2 has important roles in the cell independent of p53. It interacts with several proteins such as Rb/E2F-1 complex [], the DNA methyltransferase DNMT3A [], p107 [], MTBP []and the cyclin kinase inhibitor p21 []. MDM2 also affects cell apoptosis [, ]. The core of MDM2 folds into an open bundle of four helices which is capped by two small 3-strandedβ-sheets. It consists of a duplication of two structural repeats. MDM2 has a deep hydrophobic cleft on which the p53 α-helix binds; p53 residues involved in transactivation are buried deep within the cleft of MDM2, thereby concealing the p53 transactivation domain. In addition to its N-terminal p53 binding domain, MDM2 contains a central acidic domain, zinc finger domain and a C-terminal RING-finger domain.
MDM2 is an oncoprotein that acts as a cellular inhibitor of the p53 tumour suppressor by binding to the transactivation domain of p53 and suppressing its ability to activate transcription []. In addition, MDM2 acts as an E3 ubiquitin ligase responsible for the ubiquitination and subsequent degradation of p53 []. P53 acts in response to DNA damage, inducing cell cycle arrest and apoptosis. Inactivation of p53 is a common occurrence in neoplastic transformations. MDM2 is also known to have p53-independent functions.The core of MDM2 folds into an open bundle of four helices that is capped by two small 3-stranded β-sheets. It consists of a duplication of two structural repeats. MDM2 has a deep hydrophobic cleft on which the p53 α-helix binds; p53 residues involved in transactivation are buried deep within the cleft of MDM2, thereby concealing the p53 transactivation domain. In addition to its N-terminal p53 binding domain, MDM2 contains a central acidic domain, zinc finger domain and a C-terminal RING-finger domain.
This entry represents the central domain of the MDM2-binding protein (MTBP). MDM2 is an E3 ubiquitin-protein ligase that mediates ubiquitination of p53, leading to its degradation by the proteasome []. MTBP inhibits autoubiquitination of MDM2, thereby enhancing MDM2 stability, and this promotes MDM2-mediated ubiquitination of p53 and its subsequent degradation []. Mouse MTBP also inhibits cancer cell migration by interacting with alpha-actinin-4 (ACTN4) [].
This entry represents the N-terminal domain of the MDM2-binding protein (MTBP). MDM2 is an E3 ubiquitin-protein ligase that mediates ubiquitination of p53, leading to its degradation by the proteasome []. MTBP inhibits autoubiquitination of MDM2, thereby enhancing MDM2 stability, and this promotes MDM2-mediated ubiquitination of p53 and its subsequent degradation []. Mouse MTBP also inhibits cancer cell migration by interacting with alpha-actinin-4 (ACTN4) [].
This entry represents the C-terminal domain of the MDM2-binding protein (MTBP). MDM2 is an E3 ubiquitin-protein ligase that mediates ubiquitination of p53, leading to its degradation by the proteasome []. MTBP inhibits autoubiquitination of MDM2, thereby enhancing MDM2 stability, and this promotes MDM2-mediated ubiquitination of p53 and its subsequent degradation []. Mouse MTBP also inhibits cancer cell migration by interacting with alpha-actinin-4 (ACTN4) [].
This entry represents the MDM2-binding protein (MTBP). MDM2 is an E3 ubiquitin-protein ligase that mediates ubiquitination of p53, leading to its degradation by the proteasome []. MTBP inhibits autoubiquitination of MDM2, thereby enhancing MDM2 stability, and this promotes MDM2-mediated ubiquitination of p53 and its subsequent degradation []. Mouse MTBP also inhibits cancer cell migration by interacting with alpha-actinin-4 (ACTN4) [].
MDM2 is an E3 ubiquitin-protein ligase that mediates ubiquitination of p53/TP53, leading to its degradation by the proteasome []. p53 acts as an important defense mechanism against cancer, and is negatively regulated by interaction with the oncoprotein MDM2 []. MDM2 overexpression correlates with metastasis and advanced forms of several cancers and may be used as a cancer drug target []. In addition, MDM2 has important roles in the cell independent of p53. It interacts with several proteins such as Rb/E2F-1 complex [], the DNA methyltransferase DNMT3A [], p107 [], MTBP []and the cyclin kinase inhibitor p21 []. MDM2 also affects cell apoptosis [, ].MDM2 contains an N-terminal p53-binding domain, and a C-terminal modified C2H2C4-type RING-HC finger conferring E3 ligase activity that is required for ubiquitination and nuclear export of p53. It is also responsible for the hetero-oligomerization of MDM2, which is crucial for the suppression of P53 activity during embryonic development, and the recruitment of E2 ubiquitin-conjugating enzymes []. MDM2 also harbours a RanBP2-type zinc finger (Znf-RanBP2) domain, as well as a nuclear localisation signal (NLS) and a nuclear export signal (NES), near the central acidic region. The Znf-RanBP2 domain plays an important role in mediating MDM2 binding to ribosomal proteins and thus is involved in MDM2-mediated p53 suppression.This entry represents the C-terminal modified C2H2C4-type RING-HC finger.
This group represents a p53 negative regulator Mdm2/Mdm4.MDM2 is an oncoprotein that acts as a cellular inhibitor of the p53 tumour suppressor by binding to the transactivation domain of p53 and suppressing its ability to activate transcription []. In addition, MDM2 acts as an E3 ubiquitin ligase responsible for the ubiquitination and subsequent degradation of p53 []. P53 acts in response to DNA damage, inducing cell cycle arrest and apoptosis. Inactivation of p53 is a common occurrence in neoplastic transformations. MDM2 is also known to have p53-independent functions.The core of MDM2 folds into an open bundle of four helices which is capped by two small 3-stranded β-sheets. It consists of a duplication of two structural repeats. MDM2 has a deep hydrophobic cleft on which the p53 α-helix binds; p53 residues involved in transactivation are buried deep within the cleft of MDM2, thereby concealing the p53 transactivation domain. In addition to its N-terminal p53 binding domain, MDM2 contains a central acidic domain, zinc finger domain and a C-terminal RING-finger domain.MDM4, also known as MDMX, is a MDM2-related protein that has also been shown to inhibit p53, although not as well as MDM2. Most studies have not been able to ascribe E3 ligase function to MDM4.
ARF (also known as p14ARF in the human and p19ARF in the mouse) is an alternative transcript of the INK4a/ARF tumour-suppressor locus that encodes p16INK4a, an inhibitor of cyclin dependent kinases. ARFs are tumour suppressors participating in p53-dependent or independent pathways that restrain abnormal cell growth and maintain genomic stability [, , ]. ARF interacts with MDM2 and neutralizes MDM2's inhibition of p53 []. Mdm2 may also regulate ARF turnover by mediating its degradation through the proteasome []. p14ARF has also been shown to interact with E2F factors to form p14ARF-E2F/partner-DNA complexes repressing E2F-dependent transcription [].
This entry includes N-terminal ubiquitin-like domain from proteins such as NEDD8 ultimate buster 1.NUB1 is an adaptor protein which negatively regulates the ubiquitin-like protein Nedd8 as well as neddylated proteins levels through proteasomal degradation [, ]. It has been shown to be regulated by Mdm2 (E3 ubiquitin ligase) through ubiquitination on its lysine 159 [].
NUB1 is an adaptor protein which negatively regulates the ubiquitin-like protein Nedd8 as well as neddylated proteins levels through proteasomal degradation [, ]. It has been shown to be regulated by Mdm2 (E3 ubiquitin ligase) through ubiquitination on its lysine 159 [].
Cyclins are eukaryotic proteins that play an active role in controlling nuclear cell division cycles, and regulate cyclin dependent kinases (CDKs) [].Members of the cyclin-G subfamily of cyclins can associate with cdk5 and GAK. They also interact with the B' subclass of PP2A phosphatase and with Mdm2 and may regulate the p53-Mdm2 network []. In humans and other mammals, there are two cyclin-G subtypes - cyclin-G1 and cyclin-G2. Their expression is linked to cancer progression [, ]. This entry represents cyclin-G2 and cycling-G.
Cyclins are eukaryotic proteins that play an active role in controlling nuclear cell division cycles, and regulate cyclin dependent kinases (CDKs) [].Members of the cyclin-G subfamily of cyclins can associate with cdk5 and GAK. They also interact with the B' subclass of PP2A phosphatase and with Mdm2 and may regulate the p53-Mdm2 network []. In humans and other mammals, there are two cyclin-G subtypes - cyclin-G1 and cyclin-G2. Their expression is linked to cancer progression [, ]. This entry represents cyclin-G1.
The SWI/SNF family of complexes, which are conserved from yeast to humans, are ATP-dependent chromatin-remodelling proteins that facilitate transcription activation [, , ]. The mammalian complexes are made up of 9-12 proteins called BAFs (BRG1-associated factors). The BAF60 family have at least three members: BAF60a, which is ubiquitous, BAF60b and BAF60c, which are expressed in muscle and pancreatic tissues, respectively. BAF60b is present in alternative forms of the SWI/SNF complex, including complex B (SWIB), which lacks BAF60a. The SWIB domain is a conserved region found within the BAF60b proteins [], and can be found fused to the C terminus of DNA topoisomerase in Chlamydia. This domain is also found in the Saccharomyces cerevisiae SNF12 protein, the eukaryotic initiation factor 2 (eIF2) []and the Arabidopsis thaliana At1g31760 protein [].MDM2 is an oncoprotein that acts as a cellular inhibitor of the p53 tumour suppressor by binding to the transactivation domain of p53 and suppressing its ability to activate transcription []. p53 acts in response to DNA damage, inducing cell cycle arrest and apoptosis. Inactivation of p53 is a common occurrence in neoplastic transformations. The core of MDM2 folds into an open bundle of four helices, which is capped by two small 3-stranded β-sheets. It consists of a duplication of two structural repeats. MDM2 has a deep hydrophobic cleft on which the p53 α-helix binds; p53 residues involved in transactivation are buried deep within the cleft of MDM2, thereby concealing the p53 transactivation domain.The SWIB and MDM2 domains are homologous and share a common fold.
The SWI/SNF family of complexes, which are conserved from yeast to humans, are ATP-dependent chromatin-remodelling proteins that facilitate transcription activation [, , ]. The mammalian complexes are made up of 9-12 proteins called BAFs (BRG1-associated factors). The BAF60 family have at least three members: BAF60a, which is ubiquitous, BAF60b and BAF60c, which are expressed in muscle and pancreatic tissues, respectively. BAF60b is present in alternative forms of the SWI/SNF complex, including complex B (SWIB), which lacks BAF60a. The SWIB domain is a conserved region found within the BAF60b proteins [], and can be found fused to the C terminus of DNA topoisomerase in Chlamydia. This domain is also found in the Saccharomyces cerevisiae SNF12 protein, the eukaryotic initiation factor 2 (eIF2) []and the Arabidopsis thaliana At1g31760 protein [].MDM2 is an oncoprotein that acts as a cellular inhibitor of the p53 tumour suppressor by binding to the transactivation domain of p53 and suppressing its ability to activate transcription []. p53 acts in response to DNA damage, inducing cell cycle arrest and apoptosis. Inactivation of p53 is a common occurrence in neoplastic transformations. The core of MDM2 folds into an open bundle of four helices, which is capped by two small 3-stranded β-sheets. It consists of a duplication of two structural repeats. MDM2 has a deep hydrophobic cleft on which the p53 α-helix binds; p53 residues involved in transactivation are buried deep within the cleft of MDM2, thereby concealing the p53 transactivation domain.The SWIB and MDM2 domains are homologous and share a common fold. The core of this domain is composed of four helices arranged in an open bundle, capped by two small 3-stranded β-sheets.
Ribosomal protein L11 is one of the proteins from the large ribosomal subunit. In Escherichia coli, L11 is known to bind directly to the 23S rRNA and plays a significant role during initiation, elongation, and termination of protein synthesis. It belongs to a family of ribosomal proteins which, on the basis of sequence similarities [], groups bacteria, plant chloroplast, red algal chloroplast, cyanelle and archaeabacterial L11; and mammalian, plant and yeast L12 (YL15). L11 is a protein of 140 to 165 amino-acid residues. L11 consists of a 23S rRNA binding C-terminal domain and an N-terminal domain that directly contacts protein synthesis factors. These two domains are joined by a flexible linker that allows inter-domain movement during protein synthesis. While the C-terminal domain of L11 binds RNA tightly, the N-terminal domain makes only limited contacts with RNA and is proposed to function as a switch that reversibly associates with an adjacent region of RNA [, , , ]. In E. coli, the C-terminal half of L11 has been shown []to be in an extended and loosely folded conformation and is likely to be buried within the ribosomal structure.Ribosomal protein L11, together with proteins L10 and L7/L12, and 23S rRNA, form the L7/L12 stalk on the surface of the large subunit of the ribosome. The homologous eukaryotic cytoplasmic protein is also called 60S ribosomal protein L12, which is distinct from the L12 involved in the formation of the L7/L12 stalk. The C-terminal domain (CTD) of L11 is essential for binding 23S rRNA, while the N-terminal domain (NTD) contains the binding site for the antibiotics thiostrepton and micrococcin. L11 and 23S rRNA form an essential part of the GTPase-associated region (GAR). Based on differences in the relative positions of the L11 NTD and CTD during the translational cycle, L11 is proposed to play a significant role in the binding of initiation factors, elongation factors, and release factors to the ribosome. Several factors, including the class I release factors RF1 and RF2, are known to interact directly with L11. In eukaryotes, L11 has been implicated in regulating the levels of ubiquinated p53 and MDM2 in the MDM2-p53 feedback loop, which is responsible for apoptosis in response to DNA damage. In bacteria, the "stringent response"to harsh conditions allows bacteria to survive, and ribosomes that lack L11 are deficient in stringent factor stimulation [, , , , , , , , , , , ].
The "FY-rich"domain N-terminal (FYRN) and "FY-rich"domain C-terminal (FYRC) sequence motifs are two poorly characterised phenylalanine/tyrosine-rich regions of around 50 and 100 amino acids, respectively, that arefound in a variety of chromatin-associated proteins [, , , ]. They areparticularly common in histone H3K4 methyltransferases most notably in afamily of proteins that includes human mixed lineage leukemia (MLL) and theDrosophila melanogaster protein trithorax. Both of these enzymes play a keyrole in the epigenetic regulation of gene expression during development, andthe gene coding for MLL is frequently rearranged in infant and secondarytherapy-related acute leukemias. They are also found in transforming growthfactor beta regulator 1 (TBRG1), a growth inhibitory protein induced in cellsundergoing arrest in response to DNA damage and transforming growth factor(TGF)-beta1. As TBRG1 has been shown to bind to both the tumor suppressorp14ARF and MDM2, a key regulator of p53, it is also known as nuclearinteractor of ARF and MDM2 (NIAM). In most proteins, the FYRN and FYRC regionsare closely juxtaposed, however, in MLL and its homologues they are fardistant. To be fully active, MLL must be proteolytically processed bytaspase1, which cleaves the protein between the FYRN and FYRC regions []. TheN-terminal and C-terminal fragments remain associated after proteolysisapparently as a result of an interaction between the FYRN and FYRC regions.How proteolytic processing regulates the activity of MLL is not known.Intriguingly, the FYRN and FYRC motifs of a second family of histone H3K4methyltransferases, represented by MLL2 and MLL4 in humans and TRR inDrosophila melanogaster, are closely juxtaposed. FYRN and FYRC motifs arefound in association with modules that create or recognise histonemodifications in proteins from a wide range of eukaryotes, and it is likelythat in these proteins they have a conserved role related to some aspect ofchromatin biology [].The FYRN and FYRC regions are not separate independently folded domains, butare components of a distinct protein module, The FYRN and FYRC motifs bothform part of a single folded module (the FYR domain), which adopts an alpha+beta fold consisting of a six-stranded antiparallel β-sheet followed byfour consecutive α-helices. The FYRN region correspondsto β-strands 1-4 and their connecting loops, whereas the FYRC motif maps toβ-strand 5, β-strand 6 and helices alpha1 to alpha4. Most of theconserved tyrosine and phenylalanine residues, after which these motifs arenamed are involved in interactions that stabilise the fold. Proteins such asMLL, in which the FYRN and FYRC regions are separated by hundreds of aminoacids, are expected to contain FYR domains with a large insertion between twoof the strands of the β-sheet (strands 4 and 5) [].
The "FY-rich"domain N-terminal (FYRN) and "FY-rich"domain C-terminal (FYRC) sequence motifs are two poorly characterised phenylalanine/tyrosine-rich regions of around 50 and 100 amino acids, respectively, that arefound in a variety of chromatin-associated proteins [, , , ]. They areparticularly common in histone H3K4 methyltransferases most notably in afamily of proteins that includes human mixed lineage leukemia (MLL) and theDrosophila melanogaster protein trithorax. Both of these enzymes play a keyrole in the epigenetic regulation of gene expression during development, andthe gene coding for MLL is frequently rearranged in infant and secondarytherapy-related acute leukemias. They are also found in transforming growthfactor beta regulator 1 (TBRG1), a growth inhibitory protein induced in cellsundergoing arrest in response to DNA damage and transforming growth factor(TGF)-beta1. As TBRG1 has been shown to bind to both the tumor suppressorp14ARF and MDM2, a key regulator of p53, it is also known as nuclearinteractor of ARF and MDM2 (NIAM). In most proteins, the FYRN and FYRC regionsare closely juxtaposed, however, in MLL and its homologues they are fardistant. To be fully active, MLL must be proteolytically processed bytaspase1, which cleaves the protein between the FYRN and FYRC regions []. TheN-terminal and C-terminal fragments remain associated after proteolysisapparently as a result of an interaction between the FYRN and FYRC regions.How proteolytic processing regulates the activity of MLL is not known.Intriguingly, the FYRN and FYRC motifs of a second family of histone H3K4methyltransferases, represented by MLL2 and MLL4 in humans and TRR inDrosophila melanogaster, are closely juxtaposed. FYRN and FYRC motifs arefound in association with modules that create or recognise histonemodifications in proteins from a wide range of eukaryotes, and it is likelythat in these proteins they have a conserved role related to some aspect ofchromatin biology [].The FYRN and FYRC regions are not separate independently folded domains, butare components of a distinct protein module, The FYRN and FYRC motifs bothform part of a single folded module (the FYR domain), which adopts an alpha+beta fold consisting of a six-stranded antiparallel β-sheet followed byfour consecutive α-helices. The FYRN region correspondsto β-strands 1-4 and their connecting loops, whereas the FYRC motif maps toβ-strand 5, β-strand 6 and helices alpha1 to alpha4. Most of theconserved tyrosine and phenylalanine residues, after which these motifs arenamed are involved in interactions that stabilise the fold. Proteins such asMLL, in which the FYRN and FYRC regions are separated by hundreds of aminoacids, are expected to contain FYR domains with a large insertion between twoof the strands of the β-sheet (strands 4 and 5) [].
